title: Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion.
abstract: The aim of the study was the formulation of solid dispersions of the poorly water-soluble drug celecoxib and a polymethacrylate carrier by hot-melt extrusion. The objectives were to elucidate the mechanism of drug release from obtained extrudates and milled strands addicted to the solid-state properties of the solid dispersions and to examine and eliminate stability problems occurring under storage, exposure of mechanical stress, and in vitro dissolution. Transparent extrudates containing up to 60% drug could be prepared with a temperature setting below the melting point of celecoxib. XRPD and DSC measurements indicated the formation of a glassy solid solution, where the drug is molecularly dispersed in the carrier. The amorphous state of the glassy solid solution could be maintained during the exposure of mechanical stress in a milling process, and was stable under storage for at least 6 months. Solid-state properties and SEM images of extrudates after dissolution indicated a carrier-controlled dissolution, whereby the drug is molecularly dispersed within the concentrated carrier layer. The glassy solid solution showed a 58-fold supersaturation in 0.1 N HCl within the first 10 min, which was followed by a recrystallization process. Recrystallization could be inhibited by an external addition of HPMC.
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Albers
authors.forename: Rainer
authors.initials: R
authors.lastname: Alles
authors.forename: Karin
authors.initials: K
authors.lastname: Matthée
authors.forename: Klaus
authors.initials: K
authors.lastname: Knop
authors.forename: Julia Schulze
authors.initials: JS
authors.lastname: Nahrup
authors.forename: Peter
authors.initials: P
authors.lastname: Kleinebudde
mesh_terms: D002152:Calorimetry, Differential Scanning; D000068579:Celecoxib; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D012995:Solubility; D013449:Sulfonamides / Q000737:chemistry*; D013696:Temperature; D044366:Transition Temperature; D014961:X-Ray Diffraction
chemical_list: D016861:Cyclooxygenase Inhibitors; D004337:Drug Carriers; D005079:Excipients; D011109:Polymethacrylic Acids; D011720:Pyrazoles; D013449:Sulfonamides; C030613:polymethacrylic acid; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D000068579:Celecoxib